ART26.12, A NOVEL FATTY ACID BINDING PROTEIN 5 (FABP5) INHIBITOR, SHOWS EFFICACY IN PRECLINICAL MODELS OF PSORIASIS

Fatty acid-binding protein 5 (FABP5) is upregulated in psoriasis. This study assessed the efficacy of the potent, selective, and orally active FABP5 inhibitor ART26.12 in preclinical psoriasis models. ART26.12 (25 or 100 mg/kg BID) or BMS-986165 (TYK2 inhibitor; 10 mg/kg QD) were given orally for 10 days in the imiquimod mouse model. Imiquimod increased psoriasis-like symptoms. ART26.12 (25 mg/kg BID) and BMS-986165 comparably reduced psoriasis-like symptoms by Day 6 of IMQ treatment. Histopathology showed that ART26.12 reduced symptom severity, e.g., hyperkeratosis, parakeratosis, epidermal acanthosis, and inflammatory infiltrates. Proteomic analysis indicated ART26.12 rescued expression of fillagrin-2, promoted epidermal differentiation complex associated proteins and modulated PPAR, NF-kB, and PKC pathways likely downstream of lipid modulation. Lipidomic analysis showed widespread modulation including ceramides and linoleic acid derivatives. These data suggest ART26.12 may be a potential psoriasis treatment脂肪酸结合蛋白5（Fatty acid-binding protein 5, FABP5）在银屑病中呈上调表达。本研究评估了强效、选择性且口服活性的FABP5抑制剂ART26.12在银屑病临床前模型中的药效。在咪喹莫特（Imiquimod, IMQ）小鼠模型中，实验动物分别经口给予ART26.12（剂量为25或100 mg/kg，每日两次，BID），或酪氨酸激酶2（Tyrosine Kinase 2, TYK2）抑制剂BMS-986165（剂量为10 mg/kg，每日一次，QD），连续给药10天。咪喹莫特可诱导银屑病样症状的产生。在IMQ给药第6天时，ART26.12（25 mg/kg BID）与BMS-986165均可同等程度地减轻银屑病样症状。组织病理学检测结果显示，ART26.12可缓解症状严重程度，包括角化过度、角化不全、表皮棘层肥厚及炎性浸润等病理特征。蛋白质组学分析表明，ART26.12可恢复丝聚蛋白-2（filaggrin-2）的表达水平，促进表皮分化复合体相关蛋白的生成，并可能通过脂质调控通路下游调节过氧化物酶体增殖物激活受体（Peroxisome Proliferator-Activated Receptor, PPAR）、核因子κB（Nuclear Factor-kappa B, NF-κB）及蛋白激酶C（Protein Kinase C, PKC）的信号活性。脂质组学分析显示，ART26.12可广泛调控包括神经酰胺与亚油酸衍生物在内的多种脂质代谢物。上述研究数据表明，ART26.12有望成为银屑病的潜在治疗候选药物。